A method for synthesizing 4-acetyl-1-naphthalene carboxylic acid

Abstract

The application discloses a synthesis method of 4-acetyl-1-naphthalene carboxylic acid and belongs to the technical field of organic synthesis. The 4-acetyl-1-naphthalene carboxylic acid is prepared from 1-bromonaphthalene as a starting material. The 1-bromonaphthalene is cheap and easy to obtain. The intermediate 4-bromo-1-naphthalene ketone is obtained through a Friedel-Crafts acylation reaction. The ketal is obtained through a condensation reaction. The cyano-substituted product is obtained through a cyanylation reaction. Finally, the 4-acetyl-1-naphthalene carboxylic acid is obtained through hydrolysis. The preparation process is simple, the reaction condition is mild, the raw material is cheap and easy to obtain, the cost is low, the high-purity product can be obtained at a high yield, and the method is suitable for industrial amplification production. The method effectively solves the problems of high cost of reaction raw materials, use of expensive catalysts, dangerous reaction reagents, complex reaction steps and low product yield in the prior synthesis method.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical organic synthesis technology, specifically to a method for synthesizing 4-acetyl-1-naphthoic acid. Background Technology

[0002] Afoxolaner, CAS: 1093861-60-9, chemical name: 4-{(5R)-5-[3-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl}-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}naphthalene-1-carboxamide, molecular formula: C 26 H 17 ClF9N3O3 has a molecular weight of 625.87. The chemical structural formula of afranal is shown in formula (I): Afranal, an isoxazoline insecticide and acaricide, works by acting on ligand-gated chloride channels, particularly inhibiting channels gated by the neurotransmitter gamma-aminobutyric acid (GABA), thus blocking the transmission of chloride ions from the presynaptic to the postsynaptic membrane, leading to increased neuronal activity and over-excitation in insects, resulting in death. It is primarily used to control and prevent six major categories of common internal and external parasites, including heartworms, roundworms, hookworms, whipworms, fleas, and ticks.

[0003] 4-Acetyl-1-naphthoic acid and its derivatives are key intermediates in the synthesis of afolanar. The chemical structural formula of 4-acetyl-1-naphthoic acid is shown in formula (II): Existing technologies report a synthetic route for obtaining 4-acetyl-1-naphthoic acid from 4-acetyl-1-bromonaphthalene via cyanolation-hydrolysis. The route is as follows: The disadvantages of this route are that it requires the use of highly toxic potassium cyanide and extremely high reaction temperatures (200°C). Hydrolysis requires the use of sulfuric acid, which is highly corrosive to equipment and not conducive to industrial production.

[0004] Patent application AU2005319305 discloses a method for preparing 4-acetyl-1-naphthoic acid, the synthetic route of which is as follows: The above-mentioned synthesis method has disadvantages such as low product yield, use of the hazardous reagent methyl zinc, and the need for an anhydrous environment for some post-processing.

[0005] Existing literature (Chem Cat Chem, 2017, 9(16), 3121-3124) also discloses a method for synthesizing 4-acetyl-1-naphthoic acid, but its synthesis process requires the use of the noble metal catalyst palladium acetate and seven times the equivalent of formic acid, which has the disadvantages of high cost, low yield, and unsuitability for industrial production. Patent application CN113354530A discloses a synthesis process for 4-acetyl-1-naphthoic acid using 1,4-naphthoic acid as the starting material, through esterification-hydrolysis-condensation-hydrolysis-hydrolysis. The synthesis route is as follows: This route involves many steps and complex post-processing. Patent application CN115448831A discloses a synthetic route for obtaining 4-acetyl-1-naphthoic acid from 1-bromonaphthalene as a starting material through acetylation, ketalization, low-temperature lithiation, and hydrolysis. The synthetic route is as follows: This route uses n-butyllithium, which has high requirements for temperature, solvent water content, and reaction equipment, and actual scale-up operations may pose safety hazards. The invention patent application with publication number CN117384028A discloses a synthesis method using 1-methylnaphthalene as a starting material. First, it undergoes a Friedel-Crafts acylation reaction to obtain the intermediate 4-acetyl-1-methylnaphthalene, and then performs methyl oxidation to obtain the target product 4-acetyl-1-naphthoic acid. Its synthetic route is as follows: This method uses hydrogen peroxide as an oxidant, posing a risk of explosion. The invention patent application with publication number CN117384028A discloses a synthesis method using monomethyl 1,4-naphthalenedicarboxylic acid as a raw material, which involves acylation, condensation, and hydrolysis to prepare 4-acetyl-1-naphthoic acid. The synthetic route is as follows: The raw material for this method, 1,4-naphthalenedicarboxylic acid monomethyl ester, is expensive, which increases production costs. Summary of the Invention

[0006] This invention provides a method for synthesizing 4-acetyl-1-naphthoic acid, aiming to solve the problems of high reaction cost, hazardous reagents, low product yield, and demanding reaction conditions in existing methods for synthesizing 4-acetyl-1-naphthoic acid. At the same time, it provides a low-cost, environmentally friendly, and simple method for synthesizing 4-acetyl-1-naphthoic acid.

[0007] The purpose of this invention is to provide a method for synthesizing 4-acetyl-1-naphthoic acid, comprising the following steps: Under a protective atmosphere at -15°C to -5°C, using 1-bromonaphthalene of Formula 1 and acetic anhydride as raw materials, a Friedel-Crafts acylation reaction is carried out in a first solvent under Lewis acid catalysis to obtain 4-bromo-1-naphthyl ethyl ketone of Formula 2.

[0008] Using 4-bromo-1-naphthyl ethyl ketone, ethylene glycol, and p-toluenesulfonic acid monohydrate of Formula 2 as raw materials, a condensation reaction was carried out in a second solvent at 115℃~125℃ to obtain the compound of Formula 3.

[0009] Using the compound of formula 3 and cuprous cyanide as raw materials, a cyanidation reaction was carried out in N,N-dimethylformamide at 110℃~120℃ to obtain the compound of formula 4.

[0010] Using the compound of formula 4 as a starting material, a hydrolysis reaction was carried out in ethanol at 70℃~80℃ using sodium hydroxide and water to obtain the compound of formula 5; using the compound of formula 5 as a starting material, a hydrolysis reaction was carried out in ethanol at 70℃~80℃ using hydrochloric acid and water to obtain the compound of formula 6; the synthetic route is as follows: .

[0011] Regarding the above synthetic process, for the Friedel-Crafts acylation reaction, if the temperature is below -15℃, the Friedel-Crafts acylation rate is too slow, or even cannot be initiated, leading to incomplete reaction and a significant decrease in the yield of the intermediate 4-bromo-1-naphthyl ethylone. If the temperature is above -5℃, polyacylation or side reactions are prone to occur, generating a large number of impurities, affecting subsequent condensation and cyanation reactions, and ultimately reducing the purity and overall yield of 4-acetyl-1-naphthoic acid. When the condensation reaction temperature is below 115℃, water separation is incomplete, the reaction equilibrium shifts to the left, and the yield of the ketal intermediate is low; above 125℃, it will cause decomposition of the starting material or product. When the cyanation reaction temperature is below 110℃, cuprous cyanide has insufficient activity, and the reaction is slow and incomplete; above 120℃, it will trigger side reactions, generating coupling byproducts. Hydrolysis temperatures below 70℃ or above 80℃ will lead to runaway hydrolysis rate, decreased yield, or product degradation.

[0012] In a preferred embodiment, the molar ratio of 1-bromonaphthalene in Formula 1 to acetic anhydride is 1:1.5~1.8. If the molar ratio of acetic anhydride is less than 1.5, the acylation reagent in the Friedel-Crafts acylation reaction is insufficient, the conversion of 1-bromonaphthalene is incomplete, the intermediate yield is low, and unreacted raw materials will be carried into subsequent steps, increasing the difficulty of purification, and the impurity content in the final product increases, resulting in decreased purity. If the molar ratio of acetic anhydride is greater than 1.8, although the conversion rate can be improved, it is easy to lead to the formation of polyacylation byproducts, especially acetylation at other positions on the naphthalene ring, generating isomers of 4-acetyl-1-bromonaphthalene. These isomers are difficult to separate in subsequent reactions, seriously affecting the purity of the target product.

[0013] In a preferred embodiment, the Lewis acid is aluminum trichloride, and the molar ratio of 1-bromonaphthalene of Formula 1 to the Lewis acid is 1:3.2~3.5. If the proportion of aluminum trichloride is less than 3.2, the catalytic activity is insufficient, the Friedel-Crafts acylation reaction rate is slow, the reaction is incomplete, and the yield is reduced; at the same time, too little Lewis acid cannot effectively complex acetic anhydride, leading to a decrease in the selectivity of the acylation reaction. If the proportion of aluminum trichloride is greater than 3.5, excess Lewis acid will aggravate side reactions, such as polyacylation or debromination of the naphthalene ring, and generate a large amount of heat and acidic wastewater during post-treatment quenching, increasing operational risks, increasing the types and content of impurities in the final product, and making purification difficult.

[0014] In a preferred embodiment, the molar ratio of 4-bromo-1-naphthyl ethyl ketone, ethylene glycol, and p-toluenesulfonic acid monohydrate in Formula 2 is 1:6:0.08~0.12. If the molar ratio of ethylene glycol is lower than the specified 6, the condensation reaction equilibrium is inhibited, the yield of the ketal intermediate decreases, and unreacted 4-bromo-1-naphthyl ethyl ketone remains, which is carried into the subsequent cyanotyping reaction to generate byproducts. If the molar ratio of ethylene glycol is too high, although it can promote the reaction, it increases the burden and cost of post-processing. If the molar ratio of p-toluenesulfonic acid monohydrate is lower than the specified 0.08, the catalytic activity is insufficient, the reaction rate is slow, and the reaction time is prolonged; if it is higher than 0.12, the acidity is too strong, which will cause side reactions of other functional groups on the naphthalene ring, such as the substitution of bromine atoms or ring opening of the ketal, ultimately affecting the yield and purity of 4-acetyl-1-naphthoic acid.

[0015] In a preferred embodiment, the molar ratio of the compound of Formula 3 to cuprous cyanide is 1:1.5~1.8. If the molar ratio of cuprous cyanide is less than 1.5, the cyanation reaction is incomplete, leaving residues of the compound of Formula 3. These residues are difficult to remove in subsequent hydrolysis steps, resulting in unreacted intermediate impurities in the final product, affecting purity. If the molar ratio of cuprous cyanide is greater than 1.8, although the reaction can be ensured to be complete, excess cuprous cyanide increases the difficulty of post-processing, requiring more ammonia and ethyl acetate extraction to remove copper ions. The trace amounts of copper ions remaining in the product may affect the product color or subsequent applications, while also increasing wastewater treatment costs and environmental pressure.

[0016] In a preferred embodiment, the molar ratio of the compound of Formula 4 to sodium hydroxide is 1:3.8~4. If the molar ratio of sodium hydroxide is less than 3.8, the first hydrolysis reaction (hydrolysis of the cyano group to the amide and carboxylate) is incomplete, leaving the compound of Formula 4 or the amide intermediate. These intermediates are difficult to convert into the target carboxylic acid in the second hydrolysis, leading to a decrease in the yield of the final product. If the molar ratio of sodium hydroxide is greater than 4, although it can promote complete hydrolysis, excessive strong alkali under heating conditions can cause degradation of the naphthalene ring structure or side reactions, such as condensation of the acetyl side chain or hydroxylation of the naphthalene ring, generating colored impurities, affecting the color and purity of the product, and increasing the amount of acid used for subsequent neutralization.

[0017] In a preferred embodiment, the hydrochloric acid has a mass concentration of 36% to 38%, and the molar ratio of the compound of Formula 5 to hydrochloric acid is 1:4.2 to 4.5. If the hydrochloric acid concentration is too low or its molar ratio is below 4.2, the second hydrolysis reaction (conversion of carboxylate to carboxylic acid) will be incomplete, and the product will contain carboxylate forms of the compound of Formula 5, affecting the acidity and purity of the final product. If the hydrochloric acid concentration is too high or the molar ratio is above 4.5, although complete conversion can be guaranteed, excessive concentrated hydrochloric acid will lead to local over-acidity in post-treatment, causing the removal of acetyl groups under strongly acidic conditions or other side reactions. This also increases the amount of waste liquid to be treated and the risk of equipment corrosion, which is detrimental to industrial production.

[0018] In a preferred embodiment, the first solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,2-dichloroethane, or chloroform. If the first solvent not specified above is used, such as alcohols, esters, or water-soluble polar solvents, it will react violently (with alcohols or water) or complex (with esters) with the Lewis acid aluminum trichloride, leading to catalyst deactivation and the inability of the Friedel-Crafts acylation reaction to proceed normally. Even if the reaction is forced to proceed, the reaction selectivity will decrease due to the mismatch between solvent polarity and coordination ability, resulting in the generation of a large number of byproducts and a significant reduction in both yield and purity.

[0019] In a preferred embodiment, the second solvent is selected from toluene or xylene. If other solvents are used as the second solvent, such as chlorobenzene, acetonitrile, DMF, or DMSO, on the one hand, the unsuitable boiling point will affect the water separation effect (the condensation reaction requires reflux for water separation); on the other hand, polar solvents will interfere with the catalytic activity of p-toluenesulfonic acid or cause side reactions with the raw materials or products. For example, when DMF is used as the second solvent, it will interact with p-toluenesulfonic acid, reducing the acidic catalytic efficiency. Furthermore, DMF may decompose at high temperatures, introducing new impurities, leading to a decrease in the yield of the ketal intermediate, ultimately affecting the yield and purity of 4-acetyl-1-naphthoic acid.

[0020] In a preferred embodiment, after the Friedel-Crafts acylation reaction is completed, samples are taken for HPLC analysis, with the intermediate control standard being: 1-naphthalene bromide ≤ 3.0%. The reaction is quenched by adding prepared dilute hydrochloric acid dropwise to the reaction solution, and the temperature is controlled at T. 内 =-15℃±5℃, after dropping, raise the temperature to T 内 The mixture was stirred at 20℃±5℃ for 1-2 hours until the solids in the reaction system were completely dissolved. The mixture was then allowed to stand and separate into layers. The lower organic phase was washed successively with drinking water, sodium bicarbonate solution, and sodium chloride solution, and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure at 45℃ to obtain a light yellow oily substance, which is 4-bromo-1-naphthyl ethylone of formula 2. The crude product was not further purified and was directly added to the next reaction step.

[0021] In a preferred embodiment, after the condensation reaction is completed, a sample is sent for HPLC analysis, and the reaction solution is cooled to T. 内 At 20℃±5℃, add drinking water, stir, and allow to stand for separation. Wash the upper organic phase with drinking water, dry with anhydrous sodium sulfate, filter the organic phase, wash the filter cake with toluene, and concentrate the filtrate under reduced pressure at 60℃ to obtain a light yellow oily substance, which is the compound of formula 3. The crude product is not further purified and is directly added to the next reaction.

[0022] In a preferred embodiment, after the cyanidation reaction is completed, a sample is sent for HPLC analysis. The intermediate control standard is: the compound of formula 3 ≤ 1.0%. The reaction solution is then cooled to T. 内 =50℃±5℃, add ammonia and ethyl acetate, and maintain T 内 Stir at 20℃±5℃ for 1 hour, allow to stand and separate into layers. Extract the lower aqueous phase with ethyl acetate, combine the organic phases, and wash twice with drinking water. Add activated carbon to the organic phase and maintain a temperature of T... 内 The mixture was stirred at 20℃±5℃, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure at 50℃ to obtain a brownish-yellow solid. Anhydrous ethanol was added to the concentrate, and the temperature was raised to T. 内 =75℃±5℃, keep warm and stir for 1 hour, turn off the heating, and let it cool naturally to T. 内 =20℃±5℃, remove the oil bath, transfer to an ice bath to continue cooling to T. 内 Incubate at 5℃±5℃ for 1 hour with stirring, then filter. Use anhydrous ethanol (pre-cooled to T) to treat the filter cake. 内 Wash at 5℃±5℃, dry the filter cake under vacuum at 50℃, and collect the material to obtain a light yellow solid, which is the compound of formula 4.

[0023] After the first hydrolysis reaction is completed, a sample is sent for HPLC testing. The control standards are: compound of formula 4 ≤ 1.0%; amide intermediate ≤ 1.0%, to obtain compound of formula 5. The reaction solution is not further purified and is directly added to the next reaction.

[0024] After the second hydrolysis reaction is completed, a sample is sent for HPLC analysis. The control standard is: compounds of formula 5 ≤ 1.0%. Temperature control T. 内 At 40℃±5℃, add drinking water dropwise to the reaction solution. After the addition is complete, maintain the temperature and stir for 1 hour. Then cool the reaction system to T. 内 =20℃±5℃. Then cool down to T 内 =5℃±5℃, maintain temperature and stir. Filter, and wash the filter cake with drinking water. Vacuum dry the filter cake at 50℃ to obtain a light yellow solid, yielding the crude product of compound 6; at room temperature, add the crude product of compound 6 and acetonitrile to a three-necked flask, and heat the system to T. 内 Stir at 75℃±5℃ until the system is completely dissolved. Cool the reaction system to T.内 =20℃±5℃. Then cool down to T 内 The mixture was kept at 5℃±5℃ with stirring. It was then filtered, and the filter cake was washed with acetonitrile (pre-cooled to 5℃±5℃). The filter cake was then vacuum dried at 50℃, and the resulting material was a white solid, which is the compound of formula 6.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: To address the problems of high raw material costs, expensive catalysts, hazardous reagents, cumbersome reaction steps, and low product yield associated with traditional synthetic methods, this invention uses inexpensive and readily available 1-bromonaphthalene as the starting material. The intermediate 4-bromo-1-naphthyl ethyl ketone is obtained through Friedel-Crafts acylation, followed by ketal formation through condensation, cyanoation to obtain a cyano-substituted product, and finally hydrolysis to obtain 4-acetyl-1-naphthoic acid.

[0026] This invention uses inexpensive and readily available 1-bromonaphthalene as a starting material, replacing the expensive monomethyl 1,4-naphthalenedicarboxylate or the method requiring the use of precious metal catalysts such as palladium acetate in the prior art. Simultaneously, the cyanidation reaction uses cuprous cyanide instead of highly toxic and expensive potassium cyanide or dangerous n-butyllithium. Cuprous cyanide is low in cost and widely available, thus significantly reducing the overall production cost.

[0027] This invention uses cuprous cyanide for the cyanation reaction, and the reaction temperature is only 110℃~120℃, far lower than the 200℃ required when using potassium cyanide. The hydrolysis step uses conventional sodium hydroxide and hydrochloric acid, avoiding the use of highly corrosive sulfuric acid. Both the Friedel-Crafts acylation and condensation reactions are carried out under normal pressure and inert gas protection, without high pressure or ultra-low temperature (e.g., -78℃) operation, greatly reducing operational risks and safety hazards.

[0028] The preparation process of this invention is simple, the reaction conditions are mild, the raw materials are inexpensive and readily available, the cost is low, and it can obtain high-purity products in high yield, making it suitable for industrial-scale production. Attached Figure Description

[0029] Figure 1 The hydrogen spectrum of 4-bromo-1-naphthyl ethyl ketone of Formula 2 prepared in Example 1 of this invention.

[0030] Figure 2 The hydrogen spectrum of the compound of formula 3 prepared in Example 1 of this invention.

[0031] Figure 3 The hydrogen spectrum of the compound of formula 4 prepared in Example 1 of this invention.

[0032] Figure 4 The hydrogen spectrum of the compound of formula 6 prepared in Example 1 of this invention. Detailed Implementation

[0033] To enable those skilled in the art to better understand and implement the technical solutions of this invention, the invention is further described below with reference to specific embodiments. However, the embodiments are not intended to limit the invention. Unless otherwise specified, the following test methods and detection methods are conventional methods; unless otherwise specified, the reagents and raw materials are commercially available.

[0034] Existing methods for preparing 4-acetyl-1-naphthoic acid suffer from several drawbacks. First, they require highly toxic potassium cyanide and extremely high reaction temperatures (200°C). Hydrolysis necessitates the use of sulfuric acid, which is highly corrosive to equipment and detrimental to industrial production. Second, they suffer from low product yields, the use of hazardous reagent methyl zinc, and the need for an anhydrous environment in some post-processing steps. Third, the use of the noble metal catalyst palladium acetate and seven equivalents of formic acid results in high costs, low yields, and complex post-processing steps, making them unsuitable for industrial production. Fourth, the use of n-butyllithium places high demands on temperature, solvent moisture content, and reaction equipment, posing safety hazards during scale-up operations. Fifth, the use of hydrogen peroxide as an oxidant during the reaction poses an explosion risk. Sixth, the use of monomethyl 1,4-naphthalenedicarboxylate as a raw material is expensive, increasing production costs. Based on these technical problems, this invention provides a method for synthesizing 4-acetyl-1-naphthoic acid.

[0035] The technical solution of the present invention will be described below.

[0036] The purpose of this invention is to provide a method for synthesizing 4-acetyl-1-naphthoic acid, comprising the following steps: Under a protective atmosphere at -15°C to -5°C, using 1-bromonaphthalene of Formula 1 and acetic anhydride as raw materials, a Friedel-Crafts acylation reaction is carried out in a first solvent under Lewis acid catalysis to obtain 4-bromo-1-naphthyl ethyl ketone of Formula 2.

[0037] Using 4-bromo-1-naphthyl ethyl ketone, ethylene glycol, and p-toluenesulfonic acid monohydrate of Formula 2 as raw materials, a condensation reaction was carried out in a second solvent at 115℃~125℃ to obtain the compound of Formula 3.

[0038] Using the compound of formula 3 and cuprous cyanide as raw materials, a cyanidation reaction was carried out in N,N-dimethylformamide at 110℃~120℃ to obtain the compound of formula 4.

[0039] Using the compound of formula 4 as a starting material, a hydrolysis reaction was carried out in ethanol at 70℃~80℃ using sodium hydroxide and water to obtain the compound of formula 5; using the compound of formula 5 as a starting material, a hydrolysis reaction was carried out in ethanol at 70℃~80℃ using hydrochloric acid and water to obtain the compound of formula 6; the synthetic route is as follows: .

[0040] In the above technical solution, 1-bromonaphthalene, which is inexpensive and readily available, is used as the starting material. First, a Friedel-Crafts acylation reaction is performed to obtain the intermediate 4-bromo-1-naphthyl ethyl ketone. Then, a condensation reaction is conducted to obtain a ketal, followed by a cyanoation reaction to obtain a cyano-substituted product. Finally, hydrolysis yields 4-acetyl-1-naphthoic acid. This invention features a simple preparation process, mild reaction conditions, inexpensive and readily available raw materials, low cost, and the ability to obtain high-purity products in high yields, making it suitable for industrial-scale production.

[0041] The technical effects of the present invention will be described below through the following embodiments.

[0042] Example 1 A method for synthesizing 4-acetyl-1-naphthoic acid includes the following steps: S1, at room temperature, 4379g (3.4 eq) of aluminum trichloride and 21200g of dichloromethane were added to a 50L reactor, purged with nitrogen three times, and then cooled to T in a cold bath. 内 =-10℃, temperature control T 内 At -10℃, 1677g (1.7eq) of acetic anhydride was added dropwise. After the addition was complete, 2000g (1.0eq) of 1-bromonaphthalene was added dropwise. After the addition was complete, the reaction solution was a yellow viscous substance. After incubating the reaction at this temperature for 5 hours, samples were taken for HPLC analysis. The intermediate control standard was 1-bromonaphthalene ≤ 3.0%. The reaction was quenched by adding prepared dilute hydrochloric acid (8120g concentrated hydrochloric acid (mass concentration of 36%~38%) + 16240g drinking water) to the reaction solution, and the temperature was controlled at T. 内 =-15℃, after dropping, raise the temperature to T 内 The mixture was heated to 20℃ and stirred for 2 hours until the solid in the reaction system was completely dissolved. The mixture was then allowed to stand and separate into layers. The lower organic phase was washed successively with 4000g of drinking water, 4000g of sodium bicarbonate aqueous solution (280g sodium bicarbonate + 3720g drinking water), and 4000g of sodium chloride aqueous solution (1000g sodium chloride + 3000g drinking water), and dried with 1000g of anhydrous sodium sulfate for 1 hour. The organic phase was filtered, and the filter cake was washed with 1325g of dichloromethane. The filtrate was concentrated under reduced pressure at 45℃ to obtain 2450g of a light yellow oily substance, which is compound cpd-2. The crude product was not further purified and was directly added to the next reaction step.

[0043] S2, at room temperature, 245.0 g (1.0 eq) of compound cpd-2, 870.0 g of toluene, 359.7 g (6.0 eq) of ethylene glycol and 18.4 g (0.1 eq) of p-toluenesulfonic acid monohydrate were added to a 3 L three-necked flask. The reaction system was then heated to T. 内 The water was removed at 120℃, and the reaction was maintained at this temperature for 24 hours. A sample was then sent for HPLC analysis. The reaction solution was then cooled to T... 内At 20℃, add 400g of drinking water, stir for 30min, and let stand to separate the layers. Wash the upper organic phase with 200g of drinking water, dry with 100g of anhydrous sodium sulfate for 1h, filter the organic phase, wash the filter cake with 88.0g of toluene, and concentrate the filtrate under reduced pressure at 60℃ to obtain a light yellow oily substance, which is compound cpd-3. The crude product is not further purified and is directly added to the next reaction.

[0044] S3, at room temperature, 284.7 g (1.0 eq) of compound cpd-3, 138.4 g (1.6 eq) of cuprous cyanide, and 568.8 g of... were added to a 2 L three-necked flask. N , N -Dimethylformamide, nitrogen purging three times, reaction system heated to T 内 After reacting at 115℃ for 24 hours, samples were sent for HPLC analysis. The control standard was: compound cpd-3 ≤ 1.0%. The reaction solution was then cooled to T. 内 At 50℃, add 546.0g of ammonia and 902.0g of ethyl acetate, and maintain temperature at T. 内 Stir at 20℃ for 1 hour, allow to stand and separate into layers. Extract the lower aqueous phase with 360.8 g of ethyl acetate. Combine the organic phases and wash twice with 400 g × 2 servings of drinking water. Add 20.0 g of activated carbon to the organic phase and maintain a temperature of T... 内 The mixture was stirred at 20°C for 1 hour, filtered, and the filter cake was washed with 180.4 g of ethyl acetate. The filtrate was concentrated under reduced pressure at 50°C to obtain a brownish-yellow solid (containing a small amount of oil). N , N (-Dimethylformamide), add 473.4 g of anhydrous ethanol to the concentrate, and heat to T. 内 =75℃, keep warm and stir for 1 hour, turn off the heating, and let it cool naturally to T. 内 =20℃, remove the oil bath, transfer to an ice bath to continue cooling to T 内 =5℃, keep warm and stir for 1 hour, filter, and use 157.8g of anhydrous ethanol (pre-cooled to T) to filter cake. 内 The filter cake was washed at 5°C and then vacuum dried at 50°C for 18 hours. The resulting light yellow solid was obtained as compound cpd-4, with a yield of 75.7%.

[0045] S4, at room temperature, 145.0 g (1.0 eq) of compound cpd-4 and 228.8 g of anhydrous ethanol were added to a 2 L three-necked flask. While stirring, 145.0 g of a prepared sodium hydroxide aqueous solution ((4.0 eq) sodium hydroxide + 145.0 g drinking water) was added. The reaction system was then heated to T. 内 The reaction was carried out at 75℃ for 24 hours. Samples were sent for HPLC testing. The control standards were: compound cpd-4 ≤ 1.0%; amide intermediate ≤ 1.0%. The reaction solution of compound cpd-5 was obtained. No further purification was required, and it was directly added to the next reaction step.

[0046] S5, at room temperature, 257.2 g (4.32 eq) of concentrated hydrochloric acid was added dropwise to the reaction solution of the previous compound cpd-5, and the temperature was controlled at T. 内 =75℃. After the addition is complete, add 145.0g of drinking water and 114.4g of anhydrous ethanol. Heat the reaction system to T. 内 The reaction was carried out at 40℃ for 6 hours, and samples were sent for HPLC analysis. The control standard was: compound cpd⁻⁵ ≤ 1.0%. Temperature control T 内 At 40℃, 435.0 g of drinking water was added dropwise to the reaction solution. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction system was then cooled to T. 内 =20℃, cooling time 1 hour. Then cool down to T 内 The mixture was cooled to 5℃ for 1 hour, and then kept at that temperature with stirring for 1 hour. It was then filtered, and the filter cake was washed with 145.0 g of drinking water. The filter cake was then vacuum dried at 50℃ for 18 hours, and a light yellow solid, the crude product of compound cpd-6, was obtained, with a yield of 95.5%.

[0047] S6, at room temperature, 124.0 g of crude cpd-6 and 386.9 g of acetonitrile were added to a 1 L three-necked flask, and the system was heated to T. 内 =75℃, stir until the system is completely dissolved. Cool the reaction system to T 内 =20℃, cooling time 2 hours. Then cool down to T 内 The mixture was cooled to 5℃ for 1 hour and then stirred for 1 hour. It was then filtered, and the filter cake was washed with 96.7 g of acetonitrile (pre-cooled to 5℃). The filter cake was then vacuum dried at 50℃ for 18 hours. The material was collected to obtain a white solid, which is compound cpd-6. The yield of this purification step was 86.5%.

[0048] The above synthetic route is shown below: .

[0049] Example 2 A method for synthesizing 4-acetyl-1-naphthoic acid includes the following steps: S1, at room temperature, 4379 g (3.4 eq) of aluminum trichloride and 21200 g of 1,2-dichloroethane were added to a 50 L reactor. The reactor was purged with nitrogen three times and then cooled to T in a cold bath. 内 =-10℃, temperature control T 内 At -10℃±5℃, 1677g (1.7eq) of acetic anhydride was added dropwise. After the addition was complete, 2000g (1.0eq) of 1-bromonaphthalene was added dropwise. After the addition was complete, the reaction solution was a yellow viscous substance. After incubating the reaction at this temperature for 5 hours, samples were taken for HPLC analysis. The intermediate control standard was 1-bromonaphthalene ≤3.0%. The reaction was quenched by adding prepared dilute hydrochloric acid (8120g concentrated hydrochloric acid + 16240g drinking water) to the reaction solution, and the temperature was controlled at T.内 =-15℃, after dropping, raise the temperature to T 内 The mixture was heated to 20℃ and stirred for 1 hour until the solids in the reaction system were completely dissolved. The mixture was then allowed to stand and separate into layers. The lower organic phase was washed successively with 4000g of drinking water, 4000g of sodium bicarbonate aqueous solution (280g sodium bicarbonate + 3720g drinking water), and 4000g of sodium chloride aqueous solution (1000g sodium chloride + 3000g drinking water), and dried over 1000g of anhydrous sodium sulfate for 1 hour. The organic phase was filtered, and the filter cake was washed with 1325g of dichloromethane. The filtrate was concentrated under reduced pressure at 45℃ to obtain a light yellow oily substance, which is compound cpd-2. The crude product was not further purified and was directly added to the next reaction step.

[0050] S2, at room temperature, 245.0 g (1.0 eq) of compound cpd-2, 870.0 g of xylene, 359.7 g (6.0 eq) of ethylene glycol and 18.4 g (0.1 eq) of p-toluenesulfonic acid monohydrate were added to a 3 L three-necked flask. The reaction system was then heated to T. 内 The water was removed at 120℃, and the reaction was maintained at this temperature for 24 hours. A sample was then sent for HPLC analysis. The reaction solution was then cooled to T... 内 At 20℃, add 400g of drinking water, stir for 30min, and allow to stand for separation. Wash the upper organic phase with 200g of drinking water, dry with 100g of anhydrous sodium sulfate for 1h, filter the organic phase, wash the filter cake with 88.0g of toluene, and concentrate the filtrate under reduced pressure at 60℃ to obtain 284.7g of light yellow oily substance, which is compound cpd-3. The crude product is not further purified and is directly added to the next reaction.

[0051] S3, at room temperature, 284.7 g (1.0 eq) of compound cpd-3, 138.4 g (1.6 eq) of cuprous cyanide, and 568.8 g of [unspecified substance] were added to a 2 L three-necked flask. N , N -Dimethylformamide, nitrogen purging three times, reaction system heated to T 内 After reacting at 115℃ for 24 hours, samples were sent for HPLC analysis. The control standard was: compound cpd-3 ≤ 1.0%. The reaction solution was then cooled to T. 内 At 50℃, add 546.0g of ammonia and 902.0g of ethyl acetate, and maintain temperature at T. 内 Stir at 20℃ for 1 hour, allow to stand and separate into layers. Extract the lower aqueous phase with 360.8 g of ethyl acetate. Combine the organic phases and wash twice with 400 g × 2 servings of drinking water. Add 20.0 g of activated carbon to the organic phase and maintain a temperature of T... 内 The mixture was stirred at 20°C for 1 hour, filtered, and the filter cake was washed with 180.4 g of ethyl acetate. The filtrate was concentrated under reduced pressure at 50°C to obtain a brownish-yellow solid (containing a small amount of oil). N , N(-Dimethylformamide), add 473.4 g of anhydrous ethanol to the concentrate, and heat to T. 内 =75℃, keep warm and stir for 1 hour, turn off the heating, and let it cool naturally to T. 内 =20℃, remove the oil bath, transfer to an ice bath to continue cooling to T 内 =5℃, keep warm and stir for 1 hour, filter, and use 157.8g of anhydrous ethanol (pre-cooled to T) to filter cake. 内 The filter cake was washed at 5°C and then vacuum dried at 50°C for 18 hours. The resulting light yellow solid was obtained, which is compound cpd-4, with a yield of 72%.

[0052] S4, at room temperature, 145.0 g (1.0 eq) of compound CPD-4 and 228.8 g of anhydrous ethanol were added to a 2 L three-necked flask. While stirring, a prepared sodium hydroxide aqueous solution (145.0 g (4.0 eq) sodium hydroxide + 145.0 g drinking water) was added. The reaction system was then heated to T. 内 The reaction was carried out at 75℃ for 24 hours. Samples were sent for HPLC testing. The control standards were: compound cpd-4 ≤ 1.0%; amide intermediate ≤ 1.0%. A reaction solution containing compound cpd-5 was obtained. The reaction solution was not further purified and was directly added to the next reaction step.

[0053] S5, at room temperature, add 257.2 g (4.32 eq) of concentrated hydrochloric acid dropwise to the reaction solution containing compound cpd-5 from the previous step, and control the temperature T. 内 =75℃. After the addition is complete, add 145.0g of drinking water and 114.4g of anhydrous ethanol. Heat the reaction system to T. 内 The reaction was carried out at 40℃ for 6 hours, and samples were sent for HPLC analysis. The control standard was: compound cpd⁻⁵ ≤ 1.0%. Temperature control T 内 At 40℃, 435.0 g of drinking water was added dropwise to the reaction solution. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction system was then cooled to T. 内 =20℃, cooling time 1 hour. Then cool down to T 内 The mixture was cooled to 5℃ for 1 hour, and then stirred for 1 hour. It was filtered, and the filter cake was washed with 145.0 g of drinking water. The filter cake was then vacuum dried at 50℃ for 18 hours, and a light yellow solid was collected, which was the crude product of compound cpd-6, with a yield of 95.5%.

[0054] S6, at room temperature, 124.0 g of crude cpd-6 and 386.9 g of acetonitrile were added to a 1 L three-necked flask, and the system was heated to T. 内 =75℃, stir until the system is completely dissolved. Cool the reaction system to T 内 =20℃, cooling time 2 hours. Then cool down to T 内The mixture was cooled to 5℃ for 1 hour and then stirred for 1 hour. It was filtered, and the filter cake was washed with 96.7 g of acetonitrile (pre-cooled to 5℃). The filter cake was then vacuum dried at 50℃ for 18 hours. The product was collected to obtain a white solid, namely compound cpd-6, with a yield of 86.5%.

[0055] The above synthetic route is shown below: Example 3 A method for synthesizing 4-acetyl-1-naphthoic acid includes the following steps: S1, at room temperature, 4379 g (3.4 eq) of aluminum trichloride and 21200 g of 1,2-dichloromethane were added to a 50 L reactor. The reactor was purged with nitrogen three times and then cooled to T in a cold bath. 内 =0℃, temperature control T 内 At 0℃, 1677g (1.7eq) of acetic anhydride was added dropwise. After the addition was complete, 2000g (1.0eq) of 1-bromonaphthalene was added dropwise. After the addition was complete, the reaction solution was a yellow viscous substance. After maintaining the temperature for 5 hours, the reaction was quenched by adding prepared dilute hydrochloric acid (8120g concentrated hydrochloric acid + 16240g drinking water) dropwise. The temperature was controlled at T. 内 =0℃, after dropping, raise the temperature to T 内 The mixture was stirred at 30℃ for 1.5 hours until the solids in the reaction system were completely dissolved. The mixture was then allowed to stand and separate into layers. The lower organic phase was washed successively with 4000g of drinking water, 4000g of sodium bicarbonate aqueous solution (280g sodium bicarbonate + 3720g drinking water), and 4000g of sodium chloride aqueous solution (1000g sodium chloride + 3000g drinking water), and dried with 1000g of anhydrous sodium sulfate for 1 hour. The organic phase was filtered, and the filter cake was washed with 1325g of dichloromethane. The filtrate was concentrated under reduced pressure at 45℃ to obtain a light yellow oily substance, which is compound cpd-2. The crude product was not further purified and was directly added to the next reaction step.

[0056] S2, at room temperature, 245.0 g (1.0 eq) of compound cpd-2, 870.0 g of toluene, 186 g (6.0 eq) of methanol, and 18.4 g (0.1 eq) of p-toluenesulfonic acid monohydrate were added to a 3 L three-necked flask. The reaction system was then heated to T. 内 The water was removed at 120℃, and the reaction was maintained at this temperature for 24 hours. A sample was then sent for HPLC analysis. The reaction solution was then cooled to T... 内 At 20℃, add 400g of drinking water, stir for 30min, and let stand to separate the layers. Wash the upper organic phase with 200g of drinking water, dry with 100g of anhydrous sodium sulfate for 1h, filter the organic phase, wash the filter cake with 88.0g of toluene, and concentrate the filtrate under reduced pressure at 60℃ to obtain a light yellow oily substance, which is compound cpd-3. The crude product is not further purified and is directly added to the next reaction.

[0057] S3, at room temperature, 284.7 g (1.0 eq) of compound cpd-3, 138.4 g (1.6 eq) of cuprous cyanide and 568.8 g (3V) were added to a 2L three-necked flask. N , N -Dimethylformamide, nitrogen purging three times, reaction system heated to T 内 After reacting at 115℃ for 24 hours, a sample was taken and sent for HPLC analysis. The reaction solution was then cooled to T. 内 At 50℃, add 546.0g of ammonia and 902.0g of ethyl acetate, and maintain temperature at T. 内 Stir at 20℃ for 1 hour, allow to stand and separate into layers. Extract the lower aqueous phase with 360.8 g of ethyl acetate. Combine the organic phases and wash twice with 400 g × 2 servings of drinking water. Add 20.0 g of activated carbon to the organic phase and maintain a temperature of T... 内 The mixture was stirred at 20°C for 1 hour, filtered, and the filter cake was washed with 180.4 g of ethyl acetate. The filtrate was concentrated under reduced pressure at 50°C to obtain a brownish-yellow solid (containing a small amount of oil). N , N (-Dimethylformamide), add 473.4 g of anhydrous ethanol to the concentrate, and heat to T. 内 =75℃, keep warm and stir for 1 hour, turn off the heating, and let it cool naturally to T. 内 =20℃, remove the oil bath, transfer to an ice bath to continue cooling to T 内 =5℃, keep warm and stir for 1 hour, filter, and use 157.8g of anhydrous ethanol (pre-cooled to T) to filter cake. 内 The filter cake was washed at 5°C and then vacuum dried at 50°C for 18 hours. The material was collected to obtain a yellow solid, which is the compound cpd-4, with a yield of 61%.

[0058] S4, at room temperature, 140.0 g (1.0 eq) of compound CPD-4 and 224 g of anhydrous methanol were added to a 2 L three-necked flask. While stirring, a prepared sodium hydroxide aqueous solution (145.0 g (4.0 eq) sodium hydroxide + 145.0 g drinking water) was added. The reaction system was then heated to T. 内 The reaction was carried out at 75℃ for 24 hours. Samples were sent for HPLC testing. The control standards were: compound cpd-4 ≤ 1.0%; amide intermediate ≤ 1.0%. The reaction solution containing compound cpd-5 was not further purified and was directly added to the next reaction step.

[0059] S5, at room temperature, add 257.2 g (4.32 eq) of concentrated hydrochloric acid dropwise to the reaction solution containing compound cpd-5 from the previous step, and control the temperature T. 内 =75℃. After the addition is complete, add 145.0g of drinking water and 114.4g of anhydrous methanol. Heat the reaction system to T. 内 React at 40℃ for 6 hours. Temperature control T 内At 40℃, 435.0 g of drinking water was added dropwise to the reaction solution. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The reaction system was then cooled to T. 内 =20℃, cooling time 1 hour. Then cool down to T 内 The temperature was set to 5℃, and cooling took 1 hour. The mixture was then kept at this temperature and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with 145.0 g of drinking water. The filter cake was then vacuum-dried at 50℃ for 18 hours. The material was collected to obtain a light yellow solid, which was the crude product of compound cpd-6, with a crude product yield of 89%.

[0060] S6, at room temperature, crude cpd-6 and 350g of acetonitrile were added to a 1L three-necked flask, and the system was heated to T. 内 =75℃, stir until the system is completely dissolved. Cool the reaction system to T 内 =20℃, cooling time 2 hours. Then cool down to T 内 The mixture was cooled to 5℃ for 1 hour, and then stirred at that temperature for 1 hour. It was then filtered, and the filter cake was washed with 80 g of acetonitrile (pre-cooled to 5℃). The filter cake was then vacuum-dried at 50℃ for 18 hours and collected. A white solid was obtained, which is compound cpd-6. The yield of this purification step was 78%.

[0061] The above synthetic route is shown below: The characterization spectral data of 4-acetyl-1-naphthoic acid prepared in the above examples are as follows: Figures 1-4 As shown, the spectral data is as follows.

[0062] The NMR data for 4-bromo-1-naphthyl ethylone of Formula 2 are as follows: Figure 1 As shown: 1 H NMR (400MHz, CDCl3) δ 8.87 –8.66 (m, 1H), 8.47 – 8.28 (m, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 7.8 Hz,1H), 7.73 – 7.61 (m, 2H), 2.75 (s, 3H).

[0063] The NMR data of the compound of Formula 3 are as follows Figure 2 As shown: 1 H NMR (400 MHz, CDCl3) δ 8.82 – 8.70(m, 1H), 8.33 – 8.20 (m, 1H), 7.92 – 7.83 (m, 2H), 7.75 – 7.54 (m, 2H), 4.29– 4.09 (m, 2H), 3.94 – 3.76 (m, 2H), 1.90 (s, 3H).

[0064] The NMR data of the compound in Formula 4 are as follows: Figure 3 As shown: 1 H NMR (400 MHz, DMSO) δ 8.74 – 8.63(m, 1H), 8.18 – 8.12 (m, 2H), 7.86 – 7.74 (m, 3H), 4.16 – 4.06 (m, 2H), 3.81– 3.70 (m, 2H), 1.79 (s, 3H).

[0065] The NMR data of the compound of Formula 6 are as follows Figure 4 As shown: 1 H NMR (400 MHz, CDCl3) δ 9.17 – 9.01(m, 1H), 8.59 – 8.46 (m, 1H), 8.38 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.71 (dddd, J = 17.0, 8.3, 6.8, 1.5 Hz, 2H), 2.81 (s, 3H).

[0066] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for synthesizing 4-acetyl-1-naphthoic acid, characterized in that, Includes the following steps: Under a protective atmosphere at -15°C to -5°C, using 1-bromonaphthalene of Formula 1 and acetic anhydride as raw materials, a Friedel-Crafts acylation reaction is carried out in a first solvent under Lewis acid catalysis to obtain 4-bromo-1-naphthyl ethyl ketone of Formula 2. Using 4-bromo-1-naphthyl ethyl ketone, ethylene glycol and p-toluenesulfonic acid monohydrate of Formula 2 as raw materials, a condensation reaction was carried out in a second solvent at 115℃~125℃ to obtain the compound of Formula 3. Using the compound of formula 3 and cuprous cyanide as raw materials, a cyanidation reaction was carried out in N,N-dimethylformamide at 110℃~120℃ to obtain the compound of formula 4. Using the compound of formula 4 as a starting material, a first hydrolysis reaction was carried out in ethanol at 70℃~80℃ using sodium hydroxide and water to obtain the compound of formula 5; using the compound of formula 5 as a starting material, a second hydrolysis reaction was carried out in ethanol at 70℃~80℃ using hydrochloric acid and water to obtain the compound of formula 6; the synthetic route is as follows: 。 2. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The molar ratio of 1-bromonaphthalene to acetic anhydride in Formula 1 is 1:1.5~1.

8.

3. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The Lewis acid is aluminum trichloride, and the molar ratio of 1-bromonaphthalene of Formula 1 to the Lewis acid is 1:3.2~3.

5.

4. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The molar ratio of 4-bromo-1-naphthyl ethyl ketone, ethylene glycol and p-toluenesulfonic acid monohydrate in Formula 2 is 1:6:0.08~0.

12.

5. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The molar ratio of the compound of Formula 3 to cuprous cyanide is 1:1.5~1.

8.

6. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The molar ratio of the compound of Formula 4 to sodium hydroxide is 1:3.8~4.

7. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The hydrochloric acid has a mass concentration of 36% to 38%, and the molar ratio of the compound of Formula 5 to hydrochloric acid is 1:4.2 to 4.

5.

8. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The first solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,2-dichloroethane, or chloroform.

9. The method for synthesizing 4-acetyl-1-naphthoic acid according to claim 1, characterized in that, The second solvent is selected from toluene or xylene.

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